Drugs

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Drugs in Intensive Care

An A-Z Guide

Fourth edition

Henry G W Paw

BPharm MRPharmS MBBS FRCA Consultant in Anaesthesia and Intensive Care

York Hospital York

Rob Shulman

BSc (Pharm) MRPharmS Dip Clin Pham, DHC (Pharm) Lead Pharmacist in Critical Care University College London Hospitals

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Cambridge, New York, Melbourne, Madrid, Cape Town, Singapore, São Paulo, Delhi, Dubai, Tokyo

Cambridge University Press

The Edinburgh Building, Cambridge CB2 8RU, UK

First published in print format

ISBN-13 978-0-521-75715-7

2010

Information on this title: www.cambridge.org/9780521757157

This publication is in copyright. Subject to statutory exception and to the provision of relevant collective licensing agreements, no reproduction of any part may take place without the written permission of Cambridge University Press.

Cambridge University Press has no responsibility for the persistence or accuracy of urls for external or third-party internet websites referred to in this publication, and does not guarantee that any content on such websites is, or will remain, accurate or appropriate.

Published in the United States of America by Cambridge University Press, New York

www.cambridge.org

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Introduction vii

How to use this book viii

Abbreviations x

Acknowledgements xiii

DRUGS: An A–Z Guide 1

SHORT NOTES 229 Routes of administration 231 Loading dose 233 Drug metabolism 233 Enzyme systems 234 Drug excretion 234 Drug tolerance 235 Drug interactions 235

Therapeutic drug monitoring 236

Target range of concentration 237

Pharmacology in the critically ill 238

Cardiopulmonary resuscitation 240

Drugs in advanced life support 241

Management of acute major anaphylaxis 243

Management of severe hyperkalaemia 244

Management of malignant hyperthermia 245

Sedation, analgesia and neuromuscular blockade 247

A practical approach to sedation and analgesia 249

Management of status epilepticus 253

Treatment of status epilepticus 255

Reasons for treatment failure 256

Pseudostatus 256

Prevention of delerium tremens and alcohol

withdrawal syndrome 257

Prevention of Wernicke–Korsakoff syndrome 258

Anti-arrhythmic drugs 259

Inotropes and vasopressors 260

Bronchospasm 267

Anti-ulcer drugs 268

Immunonutrition in the ICU 268

Corticosteroids 269

Short synacthen test 270

Bone marrow rescue following nitrous oxide 270

Antioxidants 271

Post-splenectomy prophylaxis 272

Anti-microbial drugs 274

Bacterial Gram staining 278

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Extracorporeal drug clearance: basic principles 284

Drug doses in renal failure/renal replacement therapy 285

Chemical pleurodesis of malignant pleural effusion 290

APPENDICES 293

Appendix A: Creatinine clearance 295

Appendix B:Weight conversion (stones/lb to kg) 296

Appendix C: Body mass index (BMI) calculator 297

Appendix D: Lean body weight charts 298

Appendix E: Infusion rate/dose calculation 300

Appendix F: Drug compatibility chart 301

Appendix G: Omeprazole administration record 302

Appendix H: Drotrecogin prescribing criteria 304

Appendix I: Drotrecogin administration 307

Appendix J: Drotrecogin administration record 310

Appendix K: Vancomycin by continuous infusion 314

Appendix L: Child–Pugh score 316

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Since the publication of the 3rd edition in 2006, there have been several new drugs introduced to the critical care setting.This book has now been extensively updated. The main purpose of this book is to provide a practical guide that explains how to use drugs safely and effectively in a critical care setting. Doctors, nurses, pharmacists and other healthcare professionals caring for the critically ill patient will find it useful. It is not intended to list every conceivable complication and problem that can occur with a drug but to concentrate on those the clinician is likely to encounter. The book should be seen as com-plementary to, rather than replacing, the standard textbooks.

The book is composed of two main sections. The A–Z guide is the major part and is arranged alphabetically by the non-proprietary name of the drug.This format has made it easier for the user to find a partic-ular drug when in a hurry. The discussion on an individual drug is restricted to its use in the critically ill adult patient. The second part comprises short notes on relevant intensive care topics. Inside the back cover is a colour fold-out chart showing drug compatibility for intra-venous administration.

I am very fortunate to have on board a senior ICU pharmacist for this edition. While every effort has been made to check drug dosages based on a 70 kg adult and information about every drug, it is still possible that errors may have crept in. I would therefore ask readers to check the information if it seems incorrect. In addition, I would be pleased to hear from any readers with suggestions about how this book can be improved. Comments should be sent via e-mail to: [email protected].

HGWP York 2009

INTRODUCTION

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European law (directive 92/27/EEC) requires the use of the Recom-mended International Non-proprietary Name (rINN) in place of the British Approved Name (BAN). For a small number of drugs these names are different. The Department of Health requires the use of BAN to cease and be replaced by rINN, with the exceptions of adren-aline and noradrenadren-aline. For these two drugs both their BAN and rINN will continue to be used.

The format of this book was chosen to make it more ‘user friendly’ – allowing the information to be readily available to the reader in times of need. For each drug there is a brief introduction, followed by the fol-lowing categories:

Uses

This is the indication for the drug’s use in the critically ill. There will be some unlicensed use included and this will be indicated in brackets.

Contraindications

This includes conditions or circumstances in which the drug should not be used – the contraindications. For every drug, this includes known hypersensitivity to the particular drug or its constituents.

Administration

This includes the route and dosage for a 70 kg adult. For obese patients, estimated ideal body weight should be used in the calculation of the dosage (Appendix D). It also advises on dilutions and situations where dosage may have to be modified.To make up a dilution, the instruction ‘made up to 50 ml with sodium chloride 0.9%’ means that the final volume is 50 ml. In contrast, the instruction ‘to dilute with 50 ml sodium chloride 0.9%’ could result in a total volume 50 ml. It is

rec-ommended that no drug should be stored for 24 h after

reconstitu-tion or dilureconstitu-tion.

How not to use . . .

Describes administration techniques or solutions for dilution which are not recommended.

Adverse effects

These are effects other than those desired.

Cautions

Warns of situations when the use of the drug is not contraindicated but needs to be carefully watched.This will include drug-drug interactions.

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Highlights any specific problems that may occur when using the drug in a particular organ failure.

Renal replacement therapy

Provides guidance on the effects of haemofiltration/dialysis on the handling of the drug. For some drugs, data are either limited or not available.

HOW TO USE THIS BOOK

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ACE-I angiotensin-converting enzyme inhibitor

ACh acetylcholine

ACT activated clotting time

ADH antidiuretic hormone

AF atrial fibrillation

APTT activated partial thromboplastin time

ARDS acute respiratory distress syndrome

AUC area under the curve

AV atrioventricular

BP blood pressure

CABG coronary artery bypass graft

cAMP cyclic AMP

CC creatinine clearance

CMV cytomegalovirus

CNS central nervous system

CO cardiac output

COPD chronic obstructive pulmonary disease

CPR cardiopulmonary resuscitation

CSF cerebrospinal fluid

CT computerised tomography

CVP central venous pressure

CVVH continuous veno-venous haemofiltration

CVVHD continuous veno-venous haemodiafiltration

DI diabetes insipidus

DIC disseminated intravascular coagulation

DVT deep vein thrombosis

EBV Epstein–Barr virus

ECG electrocardiogram

EEG electroencephalogram

EMD electromechanical dissociation

ETCO2 end-tidal carbon dioxide concentration

FBC full blood count

FFP fresh frozen plasma

g gram

GCS Glasgow Coma Scale

GFR glomerular filtration rate

GH growth hormone

GI gastrointestinal

h hour

HOCM hypertrophic obstructive cardiomyopathy

HR heart rate

ICP intracranial pressure

ICU intensive care unit

IHD ischaemic heart disease

IM intramuscular

INR international normalised ratio

ABBREVIA

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IPPV intermittent positive pressure ventilation

IV intravenous

K potassium

kg kilogram

l litre

LFT liver function test

LH luteinising hormone

LMWH low-molecular-weight heparin

MAOI monoamine oxidase inhibitor

MAP mean arterial pressure

M6G morphine-6-glucuronide

mg milligram

MH malignant hyperthermia

MI myocardial infarction

MIC minimum inhibitory concentration

min minute

ml millilitre

MRSA meticillin-resistant Staphylococcus aureus

NG nasogastric route

ng nanogram

NJ nasojejunal

nocte at night

NSAID non-steroidal anti-inflammatory drug

PaCO2 partial pressure of carbon dioxide in arterial blood

PaO2 partial pressure of oxygen in arterial blood

PCAS patient-controlled analgesia system

PCI percutaneous coronary intervention

PCP Pneumocystis carinii pneumonia

PCWP pulmonary capillary wedge pressure

PD peritoneal dialysis

PE pulmonary embolism

PEA pulseless electrical activity

PEG percutaneous endoscopic gastrostomy

PEJ percutaneous endoscopic jejunostomy

PO per orum (by mouth)

PR per rectum (rectal route)

PRN pro re nata (as required)

PVC polyvinyl chloride

PVD peripheral vascular disease

RR respiratory rate

s second

SC subcutaneous

SIRS systemic inflammatory response syndrome

SL sublingual

SSRI selective serotonin re-uptake inhibitors

STEMI ST-segment elevation myocardial infarction

SVR systemic vascular resistance

ABBREVIA

TIONS

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TFT thyroid function test

TNF tumour necrosis factor

TPN total parenteral nutrition

U&E urea and electrolytes

VF ventricular fibrillation

VRE vancomycin-resistant Enterococcus faecium

VT ventricular tachycardia

WFI water for injection

WPW syndrome Wolff–Parkinson–White syndrome

ABBREVIA

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I would like to thank all my colleagues from whom I have sought advice during the preparation of this book. In particular, I acknowledge the assistance of our own Critical Care Pharmacist Stuart Parkes, and Drs Peter Stone, Neil Todd and Joy Baruah.

ACKNOWLEDGEMENTS

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Drugs:

An A–Z Guide

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Acetazolamide is a carbonic anhydrase inhibitor normally used to reduce intra-ocular pressure in glaucoma. Metabolic alkalosis may be partially corrected by the use of acetazolamide. The most common cause of metabolic alkalosis on the ICU is usually the result of furosemide administration.

Uses

Metabolic alkalosis (unlicensed)

Hypokalaemia Hyponatraemia

Hyperchloraemic acidosis Severe liver failure Renal failure

Sulphonamide hypersensitivity

Administration

• IV: 250–500 mg, given over 3–5 min every 8 hours

Reconstitute with 5 ml WFI

Monitor: FBC, U&E and acid/base balance

How not to use acetazolamide

IM injection – painful Not for prolonged use

Adverse effects

Metabolic acidosis

Electrolyte disturbances (hypokalaemia and hyponatraemia) Blood disorders

Abnormal LFT

Cautions

Avoid extravasation at injection site (risk of necrosis) Avoid prolonged use (risk of adverse effects)

Concurrent use with phenytoin ( serum level of phenytoin)

Organ failure

Renal: avoid if possible (metabolic acidosis) ↓

A

ACET

AZOLAMIDE

3 Hepatic: avoid (abnormal LFT)

CC (ml/min) Dose (mg) Interval (h)

20–50 250 Up to 6

10–20 250 Up to 12

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ACETYLCYSTEINE (Parvolex)

Acetylcysteine is an effective antidote to paracetamol if administered within 8 hours after an overdose.Although the protective effect dimin-ishes progressively as the overdose–treatment interval increases, acetyl-cysteine can still be of benefit up to 24 hours after the overdose. In paracetamol overdose the hepatotoxicity is due to formation of a toxic metabolite. Hepatic reduced glutathione inactivates the toxic metabo-lite by conjugation, but glutathione stores are depleted with hepato-toxic doses of paracetamol. Acetylcysteine, being a sulphydryl (SH) group donor, protects the liver probably by restoring depleted hepatic reduced glutathione or by acting as an alternative substrate for the toxic metabolite.

Acetylcysteine may have significant cytoprotective effects.The cellular damage associated with sepsis, trauma, burns, pancreatitis, hepatic failure and tissue reperfusion following acute MI may be mediated by the formation and release of large quantities of free radicals that overwhelm and deplete endogenous antioxidants (e.g. glutathione). Acetylcysteine is a scavenger of oxygen free radicals. In addition, acetylcysteine is a glutathione precursor capable of replenishing depleted intracellular glutathione and, in theory, augmenting antioxidant defences (p. 271).

Acetylcysteine can be used to reduce the nephrotoxic effects of intra-venous contrast media. Possible mechanisms include scavenging a variety of oxygen-derived free radicals and the improvement of endothelium-dependent vasodilation.

Nebulised acetylcysteine can be used as a mucolytic agent. It reduces sputum viscosity by disrupting the disulphide bonds in the mucus gly-coproteins and enhances mucociliary clearance, thus facilitating easier expectoration.

Uses

Paracetamol overdose Antioxidant (unlicensed)

Prevent contrast-induced nephropathy (unlicensed)

Reduce sputum viscosity and facilitate easier expectoration (unli-censed)

As a sulphydryl group donor to prevent the development of nitrate tol-erance (unlicensed)

A

ACETYLCYSTEINE (Par

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A

ACETYLCYSTEINE (Par

volex)

5

Weight (kg) Initial Second Third

150 mg/kg 50 mg/kg in 100 mg/kg

in 200 ml 500 ml in 1 litre glucose 5% glucose 5% glucose 5% over 15 min over 4 h over 16 h Parvolex (ml) Parvolex (ml) Parvolex (ml)

50 37.5 12.5 25 60 45.0 15.0 30 70 52.5 17.5 35 80 60.0 20.0 40 90 67.5 22.5 45 x 0.75x 0.25x 0.5x

For children 20 kg: same doses and regimen but in half the quantity of IV fluid

Administration

Paracetamol overdose

• IV infusion: 150 mg/kg in 200 ml glucose 5% over 15 min, followed

by 50 mg/kg in 500 ml glucose 5% over 4 h, then 100 mg/kg in 1 litre glucose 5% over the next 16 h

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A

ACETYLCYSTEINE (Par

volex)

Patients whose plasma concentrations fall on or above treatment line A should receive acetylcysteine. Patients with induced hepatic microso-mal oxidase enzymes (for chronic alcoholics and patients taking enzyme-inducing drugs, see p. 234) are susceptible to paracetamol-induced hepatotoxicity at lower paracetamol concentrations and should be assessed against treatment line B.

1.3 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24

Hours after ingestion TREATMENT LINES Plasma paracetamol (mmol/l) Plasma paracetamol (mg/l) 1.2 1.1 1.0 0.9 A

Normal treatment line

B High risk treatment line

0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 Treatment nomogram

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A

ACETYLCYSTEINE (Par

volex)

7 Antioxidant

• IV infusion: 75–100 mg/kg in 1 litre glucose 5%, give over 24 h (rate

40 ml/h)

Prevent contrast-induced nephropathy

• IV bolus 1200 mg pre-contrast, then after 12 hours 1200 mg PO/NG (or IV if nil-by-mouth) 12 hourly for 48 hours

Reduce sputum viscosity

• Nebulised: 4 ml (800 mg) undiluted Parvolex (20%) driven by air,

8 hourly

Administer before chest physiotherapy

How not to use acetylcysteine

Do not drive nebuliser with oxygen (oxygen inactivates acetylcysteine)

Adverse effects

Anaphylactoid reactions (nausea, vomiting, flushing, itching, rashes, bronchospasm, hypotension)

Fluid overload

Cautions

Asthmatics (risk of bronchospasm) Pulmonary oedema (worsens)

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ACICLOVIR (Zovirax)

Interferes with herpes virus DNA polymerase, inhibiting viral DNA replication.Aciclovir is renally excreted and has a prolonged half-life in renal impairment.

Uses

Herpes simplex virus infections:

• HSV encephalitis

• HSV genital, labial, peri-anal and rectal infections

Varicella zoster virus infections:

• Beneficial in the immunocompromised patients when given IV

within 72 hours: prevents complications of pneumonitis, hepatitis or thrombocytopenia

• In patients with normal immunity, may be considered if the

oph-thalmic branch of the trigeminal nerve is involved

Not suitable for CMV or EBV infections

Administration

• IV: 5–10 mg/kg 8 hourly

Available in 250 mg/10 ml and 500 mg/20 ml ready-diluted or in 250 mg and 500 mg vials for reconstitution.

Reconstitute 250 mg vial with 10 ml WFI or sodium chloride 0.9% (25 mg/ml).

Reconstitute 500 mg vial with 20 ml WFI or sodium chloride 0.9% (25 mg/ml).

Take the reconstituted solution (25 mg/ml) and make up to 50 ml (for 250 mg vial) or 100 ml (for 500 mg vial) with sodium chloride 0.9% or glucose 5%, and give over 1 hour.

Ensure patient is well hydrated before treatment is administered. If fluid-restricted, can give centrally via syringe pump undiluted (unlicensed).

In renal impairment:

A

ACICLOVIR (Zovirax)

CC (ml/min) Dose (mg/kg) Interval (h)

25–50 5–10 12

10–25 5–10 24

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A

ACICLOVIR (Zovirax)

9

How not to use aciclovir

Rapid IV infusion (precipitation of drug in renal tubules leading to renal impairment)

Adverse effects

Phlebitis

Reversible renal failure Elevated liver function tests

CNS toxicity (tremors, confusion and fits)

Cautions

Concurrent use of methotrexate Renal impairment (reduce dose)

Dehydration/hypovolaemia (renal impairment due to precipitation in renal tubules)

CVVH dose as for CC 10–25 ml/min, i.e 5–10 mg/kg IV every 24 hours (some units use 3.5–7 mg/kg every 24 hours). Not significantly cleared by PD or HD, dose as if CC 10 ml/min, i.e. 2.5–5 mg/kg IV every 24 hours.The dose is dependent upon the indication.

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ADENOSINE (Adenocor)

This endogenous nucleoside is safe and effective in ending90% of

re-entrant paroxysmal SVT. However, this is not the most common type of SVT in the critically ill patient.After an IV bolus effects are

immedi-ate (10–30 seconds), dose-relimmedi-ated and transient (half-life10 s; entirely

eliminated from plasma in 1 minute, being degraded by vascular endothelium and erythrocytes). Its elimination is not affected by renal/hepatic disease. Adenosine works faster and is superior to vera-pamil. It may be used in cardiac failure, in hypotension and with -blockers, in all of which verapamil is contraindicated.

Uses

It has both therapeutic and diagnostic uses:

• Alternative to DC cardioversion in terminating paroxysmal SVT,

including those associated with WPW syndrome

• Determining the origin of broad complex tachycardia; SVT responds,

VT does not (predictive accuracy 92%; partly because VT may occa-sionally respond).Though adenosine does no harm in VT, verapamil may produce hypotension or cardiac arrest

Second- or third-degree heart block (unless pacemaker fitted) Sick sinus syndrome (unless pacemaker fitted)

Asthmatic – may cause bronchospasm

Patients on dipyridamole (drastically prolongs the half-life and enhances the effects of adenosine – may lead to dangerously prolonged high-degree AV block)

Administration

• Rapid IV bolus: 3mg over 1–2 seconds into a large vein, followed by rapid flushing with sodium chloride 0.9%

If no effect within 2 min, give 6 mg If no effect within 2 min, give 12 mg If no effect, abandon adenosine Need continuous ECG monitoring

More effective given via a central vein or into right atrium

How not to use adenosine

Without continuous ECG monitor

Adverse effects

Flushing (18%), dyspnoea (12%) and chest discomfort are the

com-monest side-effects but are well tolerated and invariably last1 min.

If given to an asthmatic and bronchospasm occurs, this may last up to 30 min (use aminophylline to reverse).

A

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A

ADENOSINE (Adenocor)

11

Cautions

AF or atrial flutter with accessory pathway ( conduction down anom-alous pathway may increase)

Early relapse of paroxysmal SVT is more common than with verapamil but usually responds to further doses

Adenosine’s effect is enhanced and extended by dipyridamole – if essential to give with dipyridamole, reduce initial dose to 0.5–1 mg

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ADRENALINE

Both - and -adrenergic receptors are stimulated. Low doses tend to

produce predominantly -effects while higher doses tend to produce

pre-dominantly -effects. Stimulation of 1-receptors in the heart increases

the rate and force of contraction, resulting in an increase in cardiac

out-put. Stimulation of 1-receptor causes peripheral vasoconstriction, which

increases the systolic BP. Stimulation of 2-receptors causes

broncho-dilatation and vasobroncho-dilatation in certain vascular beds (skeletal muscles). Consequently, total systemic resistance may actually fall, explaining the decrease in diastolic BP that is sometimes seen.

Uses

Low cardiac output states Bronchospasm

Cardiac arrest (p. 241) Anaphylaxis (p. 243)

Before adequate intravascular volume replacement

Administration

Low cardiac output states

Dose: 0.01–0.30µg/kg/min IV infusion via a central vein

Titrate dose according to HR, BP, cardiac output, presence of ectopic beats and urine output

4 mg made up to 50 ml glucose 5%

Dosage chart (ml/h)

A

ADRENALINE

Weight (kg) Dose (g/kg/min)

0.02 0.05 0.1 0.15 0.2 50 0.8 1.9 3.8 5.6 7.5 60 0.9 2.3 4.5 6.8 9.0 70 1.1 2.6 5.3 7.9 10.5 80 1.2 3.0 6.0 9.0 12 90 1.4 3.4 6.8 10.1 13.5 100 1.5 3.8 7.5 11.3 15.0 110 1.7 4.1 8.3 12.4 16.5 120 1.8 4.5 9.0 13.5 18.0

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Bronchospasm

• 0.5–1 mg nebulised PRN

• 0.5–1 ml of 1:1000 (0.5–1 mg) made up to 5 ml with sodium chlo-ride 0.9%

Cardiac arrest (p. 241)

• IV bolus: 10 ml 1 in 10 000 solution (1 mg)

Anaphylaxis (p. 243)

• IV bolus: 0.5–1.0 ml 1 in 10 000 solution (50–100µg), may be

repeated PRN, according to BP

How not to use adrenaline

In the absence of haemodynamic monitoring

Do not connect to CVP lumen used for monitoring pressure (surge of drug during flushing of line)

Incompatible with alkaline solutions, e.g. sodium bicarbonate, furosemide, phenytoin and enoximone

Adverse effects

Arrhythmia Tachycardia Hypertension Myocardial ischaemia Increased lactate levels

Cautions

Acute myocardial ischaemia or MI

A

ADRENALINE

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ALFENTANIL

It is an opioid 30 times more potent than morphine and its duration is shorter than that of fentanyl. The maximum effect occurs about 1 min after IV injection. Duration of action following an IV bolus is between 5 and 10 min. Its distribution volume and lipophilicity are lower than fentanyl. It is ideal for infusion and may be the agent of choice in renal failure.The context-sensitive half-life may be prolonged following IV infusion. In patients with hepatic failure the elimination half-life may be markedly increased and a prolonged duration of action may be seen.

Uses

Patients receiving short-term ventilation

Airway obstruction Concomitant use of MAOI

Administration

• IV bolus: 500µg every 10 min as necessary

• IV infusion rate: 1–5 mg/h (up to 1g/kg/min)

Draw ampoules up neat to make infusion, i.e. 0.5 mg/ml or dilute to a convenient volume with glucose 5% or sodium chloride 0.9%

How not to use alfentanil

In combination with an opioid partial agonist, e.g. buprenorphine (antagonizes opioid effects)

Adverse effects

Respiratory depression and apnoea Bradycardia

Nausea and vomiting Delayed gastric emptying Reduce intestinal mobility Biliary spasm

Constipation Urinary retention

Chest wall rigidity (may interfere with ventilation)

A

ALFENT

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Cautions

Enhanced sedative and respiratory depression from interaction with:

• benzodiazepines

• antidepressants

• anti-psychotics

Avoid concomitant use of and for 2 weeks after MAOI discontinued (risk of CNS excitation or depression – hypertension, hyperpyrexia, convulsions and coma)

Head injury and neurosurgical patients (may exacerbate ICP as a

result of PaCO2)

Erythromycin (↓ clearance of alfentanil)

Organ failure

Respiratory: respiratory depression

Hepatic: enhanced and prolonged sedative effect ↓ ↓ ↓

A

ALFENT

ANIL

15

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ALTEPLASE (Actilyse)

The use of thrombolytics is well established in myocardial infarction. They act by activating plasminogen to form plasmin, which degrades fibrin and so breaks up thrombi. Alteplase or tissue-type plasminogen activator (rt-PA) can be used in major pulmonary embolism associated with hypoxia and haemodynamic compromise.Whilst alteplase is more expensive than streptokinase, it is the preferred thrombolytic as it does not worsen hypotension. Severe bleeding is a potential adverse effect of alteplase and requires discontinuation of the thrombolytic and may require administration of coagulation factors and antifibrinolytic drugs (such as tranexamic acid).

Uses

Major pulmonary embolism Acute myocardial infarction Acute stroke

Recent haemorrhage, trauma or surgery Coagulation defects

Severe hypertension Oesophageal varices Severe liver disease Acute pancreatitis

Administration

• Pulmonary embolism

IV: 10 mg, given over 1–2 minutes, followed by IV infusion of 90 mg over 2 hours

Dissolve in WFI to a concentration of 1 mg/ml (50-mg vial with 50 ml WFI). Foaming may occur; this will dissipate after standing for a few minutes.

Monitor: BP (treat if systolic BP 180 mmHg or diastolic BP

105 mmHg) • Myocardial infarction

Accelerated regimen (initiated within 6 hours of symptom onset), 15 mg IV, then 50 mg IV infusion over 30 min, then 35 mg over 60 min (total dose 100 mg over 90 min); in patients 65 kg,15 mg by IV, the IV infusion of 0.75 mg/kg over 30 min, then 0.5 mg/kg over 60 min (max. total dose 100 mg over 90 min)

Myocardial infarction, initiated within 6–12 hours of symptom onset, 10 mg IV, followed by IV infusion of 50 mg over 60 min, then 4 infusions each of 10 mg over 30 min (total dose 100 mg over 3 hours; max. 1.5 mg/kg in patients 65 kg)

A

AL

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• Acute stroke

Treatment must begin within 3 hours of symptom onset.

IV: 900 g/kg (max. 90 mg), initial 10% of dose by IV injection over 3 min, remainder by IV infusion over 60 min.

Not recommended in the elderly over 80 years of age

How not to use alteplase

Not to be infused in glucose solution

Adverse effects

Nausea and vomiting Bleeding

Cautions

Acute stroke (risk of cerebral bleed) Diabetic retinopathy (risk of retinal bleeding)

Abdominal aortic aneurysm and enlarged left atrium with AF (risk of embolisation)

Organ failure

Renal: risk of hyperkalaemia Hepatic: avoid in severe liver failure

A

AL

TEPLASE (Actilyse)

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AMINOPHYLLINE

The ethylenediamine salt of theophylline. It is a non-specific inhibitor of phosphodiesterase, producing increased levels of cAMP. Increased cAMP levels result in:

• Bronchodilation

• CNS stimulation

• Positive inotropic and chronotropic effects

• Diuresis

Theophylline has been claimed to reduce fatigue of diaphragmatic muscles

Uses

Prevention and treatment of bronchospasm

Uncontrolled arrhythmias Hyperthyroidism

Administration

• Loading dose: 5 mg/kg IV, given over 30 min, followed by

mainte-nance dose 0.1–0.8 mg/kg/h

Dilute 1 g (40 ml) aminophylline (25 mg/ml) in 460 ml glucose 5% or sodium chloride 0.9% to give a concentration of 2 mg/ml

No loading dose if already on oral theophylline preparations (toxicity) Reduce maintenance dose (0.1–0.3 mg/kg/h) in the elderly and patients with congestive heart failure and liver disease

Increase maintenance dose (0.8–1 mg/kg/h) in children (6 months– 16 years) and young adult smokers

Monitor plasma level (p. 236)

Therapeutic range 55–110 mmol/l or 10–20 mg/l

The injection can be administered nasogastrically (unlicensed). This may be useful as there is no liquid preparation of aminophylline or theophylline.To convert from IV to NG, keep the total daily dose the same, but divide into four equal doses.Aminophylline modified-release tablets are taken by mouth twice daily.Alternatively, if these are crushed up to go down a nasogastric tube then they will lose their slow-release characteristic and will need to be administered four times per day keeping the total daily dose the same.

A

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A

AMINOPHYLLINE

19

How not to use aminophylline

Rapid IV administration (hypotension, arrhythmias)

Adverse effects

Tachycardia Arrhythmias Convulsions

Cautions

Subject to enzyme inducers and inhibitors (p. 234)

Concurrent use of erythromycin and ciprofloxacin: reduce dose

Organ failure

Cardiac: prolonged half-life (reduce dose) Hepatic: prolonged half-life (reduce dose)

Dose: mg/kg/hour Weight: kg 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1 50 2.5 5 7.5 10 12.5 15 17.5 20 22.5 25 60 3 6 9 12 15 18 21 24 27 30 70 3.5 7 10.5 14 17.5 21 24.5 28 31.5 35 80 4 8 12 16 20 24 28 32 36 40 90 4.5 9 13.5 18 22.5 27 31.5 36 40.5 45 100 5 10 15 20 25 30 35 40 45 50 110 5.5 11 16.5 22 27.5 33 38.5 44 49.5 55 120 6 12 18 24 30 36 42 48 54 60

• Elderly • Usual adult maintenance • Children

• Congestive • Young adult

Heart failure smokers

• Liver disease

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A

AMIODARONE

Amiodarone has a broad spectrum of activity on the heart. In addition to having an anti-arrhythmic activity, it also has anti-anginal effects. This may result from its - and -adrenoceptor-blocking properties as well as from its calcium channel-blocking effect in the coronary vessels. It causes minimal myocardial depression. It is therefore often a first-line drug in critical care situations. It has an extremely long half-life (15–105 days). Unlike oral amiodarone, IV administration usually acts relatively rapidly (20–30 min). Oral bioavailability is 50%, therefore 600 mg PO/NG is equivalent to 300 mg IV. Overlap the initial oral and IV therapy for 16 to 24 hours. An oral loading dose regimen is neces-sary even when the patient has been adequately ‘loaded’ intravenously. This is because amiodarone has a large volume of distribution (4000 l) and a long half-life. The high initial plasma levels quickly dissipate as the drug binds to the peripheral lipophilic tissues. Thus a pro-longed loading regimen is required.When the cause of the arrhythmia has resolved, e.g. sepsis, then amiodarone treatment can be stopped abruptly.

Uses

Good results with both ventricular and supraventricular arrhythmias, including those associated with WPW syndrome.

Iodine sensitivity (amiodarone contains iodine) Sinus bradycardia (risk of asystole)

Heart block (unless pacemaker fitted)

Administration

• Loading: 300 mg in 25–250 ml glucose 5% IV over 20–120 min,

followed by 900 mg in 50–500 ml glucose 5% over 24 hours. If fluid-restricted, up to 900 mg can be diluted in 50 ml glucose 5% and administered centrally

• Maintenance: 600 mg IV daily for 7 days, then 400 mg IV daily for

7 days, then 200 mg IV daily

Administer IV via central line. A volumetric pump should be used as the droplet size of amiodarone may be reduced.

Continuous cardiac monitoring

• Oral: 200 mg 8 hourly for 7 days, then 200 mg 12 hourly for 7 days,

then 200 mg daily

How not to use amiodarone

Incompatible with sodium chloride 0.9% Do not use via peripheral vein (thrombophlebitis)

(37)

Adverse effects Short-term

Skin reactions common

Vasodilation and hypotension or bradycardia after rapid infusion Corneal microdeposits (reversible on stopping)

Long-term

Pulmonary fibrosis, alveolitis and pneumonitis (usually reversible on stopping)

Liver dysfunction (asymptomatic in LFT common) Hypo- or hyperthyroidism (check TFT before starting drug) Peripheral neuropathy, myopathy and cerebellar dysfunction (reversible on stopping)

Cautions

Increased risk of bradycardia, AV block and myocardial depression with -blockers and calcium-channel antagonists

Potentiates the effect of digoxin, theophylline and warfarin – reduce dose

Organ failure

Hepatic: worsens

Renal: accumulation of iodine may risk of thyroid dysfunction↓

↓

A

AMIODARONE

(38)

AMITRIPTYLINE

A tricyclic antidepressant with sedative properties.When given at night it will help to promote sleep. It may take up to 4 weeks before any bene-ficial antidepressant effect is seen.

Uses

Depression in patients requiring long-term ICU stay, particularly where sedation is required

Difficulty with sleep

Neuropathic pain (unlicensed indication)

Recent myocardial infarction Arrhythmia

Heart block Severe liver disease

Administration

• Oral: depression 25–75 mg nocte

Neuropathic pain 10–25 mg at night, increased if necessary up to 75 mg daily

How not to use amitriptyline

During the daytime (disturbs the normal sleep pattern)

Adverse effects

Antimuscarinic effects (dry mouth, blurred vision, urinary retention) Arrhythmias

Postural hypotension Confusion

Hyponatraemia

Cautions

Cardiac disease (risk of arrhythmias) Hepatic failure

Acute angle glaucoma

Avoid long-term use if patient represents a suicide risk Concurrent use of MAOI

Additive CNS depression with other sedative agents May potentiate direct-acting sympathomimetic drugs

Prostatic hypertrophy–urinary retention (unless patient’s bladder catheterized)

Organ failure

CNS: sedative effects increased Hepatic: sedative effects increased

A

(39)

AMPHOTERICIN (Fungizone)

Amphotericin is active against most fungi and yeasts. It also has useful activity against protozoa, including Leishmania spp., Naeglaria and Hartmanella. It is not absorbed from the gut when given orally.When given IV it is highly toxic and side-effects are common.The liposomal and colloidal formulations are less toxic, particularly in terms of nephrotoxicity.

Uses

Suppress gut carriage of Candida species by the oral route Severe systemic fungal infections:

Aspergillosis Candidiasis Coccidiomycosis Cryptococcosis Histoplasmosis Administration

• Oral: suppression of gut carriage of Candida

100–200 mg 6 hourly

• IV: systemic fungal infections

Initial test dose of 1 mg given over 30 min, then 250g/kg daily,

gradually increased if tolerated to 1 mg/kg daily over 4 days

• For severe infection: 1 mg/kg daily or 1.5 mg/kg daily on alternate

days

Available in 20-ml vial containing 50 mg amphotericin

Reconstitute with 10 ml WFI (5 mg/ml). Add phosphate buffer to the glucose 5% bag before amphotericin is added. The phosphate buffer label will state the volume to be added; then further dilute the reconstituted solution as follows:

For peripheral administration:

Dilute further with 500 ml glucose 5% (to 0.2 mg/ml) Give over 6 hours

For central administration:

Dilute further with 50–100 ml glucose 5% Give over 6 hours

Prolonged treatment usually needed (duration depends on severity and nature of infection)

Monitor:

Serum potassium, magnesium and creatinine FBC

LFT

A

AMPHOTERICIN (Fungizone)

(40)

How not to use amphotericin

Must not be given by rapid IV infusion (arrhythmias) Not compatible with sodium chloride

There are several formulations of IV amphotericin and they are not interchangeable. Errors of this sort have caused lethal consequences or subtherapeutic doses.

Adverse effects

Fever and rigors – common in first week. May need paracetamol, chlorphenamine and hydrocortisone premedication

Nephrotoxicity – major limiting toxicity. Usually reversible Hypokalaemia/hypomagnesaemia – 25% will need supplements Anaemia (normochromic, normocytic) – 75%. Due to bone marrow suppression

Cardiotoxicity – arrhythmias and hypotension with rapid IV bolus Phlebitis – frequent change of injection site

Pulmonary reactions

GI upset – anorexia, nausea, vomiting

Cautions

Kidney disease

Concurrent use of other nephrotoxic drugs Hypokalaemia – increased digoxin toxicity

Avoid concurrent administration of corticosteroids (except to treat febrile and anaphylactic reactions)

Organ failure

Renal: use only if no alternative; nephrotoxicity may be reduced with use of Amphocil or AmBisome

No further dose modification is required during renal replacement therapy

A

(41)

AMPHOTERICIN (COLLOIDAL) –

Amphocil

Amphotericin is active against most fungi and yeasts. It also has useful activity against protozoa, including Leishmania spp., Naeglaria and

Hartmanella. Amphocil is a colloidal formulation containing a stable

complex of amphotericin and sodium cholesteryl sulphate. It is available in vials containing either 50 or 100 mg amphotericin.This renders the drug less toxic to the kidney than the parent compound. Deterioration in renal function attributable to Amphocil is rare.

Uses

Severe systemic fungal infections, when conventional amphotericin is contraindicated because of toxicity, especially nephrotoxicity.

Administration

• IV infusion: start at 1 mg/kg once daily, increasing to 3–4 mg/kg

once daily, given over 60–90 min

Amphocil must be initially reconstituted by adding WFI: 50-mg vial – add 10 ml WFI

100-mg vial – add 20 ml WFI

The liquid in each reconstituted vial will contain 5 mg/ml ampho-tericin.This is further diluted to a final concentration of 0.625 mg/ml by diluting 1 volume of the reconstituted Amphocil with 7 volumes glucose 5%.

Flush an existing intravenous line with glucose 5% before infusion. Although anaphylactic reactions rare, before starting treatment, an ini-tial test dose of 2 mg should be given over 10 min, infusion stopped and patient observed for 30 min. Continue infusion if no signs of anaphyl-actic reaction.

Monitor: serum potassium and magnesium.

In renal dialysis patients, give Amphocil at the end of each dialysis.

How not to use colloidal amphotericin

Do not mix with other drugs

Adverse effects

Prevalence and severity lower than conventional amphotericin

A

AMPHOTERICIN (COLLOIDAL) – Amphocil

(42)

Cautions

Kidney disease

Concurrent use of nephrotoxic drugs

Diabetes: Amphocil contains lactose monohydrate 950 mg/50-mg vial or 1900 mg/100-mg vial (may cause hyperglycaemia)

A

(43)

AMPHOTERICIN (LIPOSOMAL) –

AmBisome

Amphotericin is active against most fungi and yeasts. It also has useful activity against protozoa, including Leishmania spp., Naeglaria and

Hartmanella. AmBisome is a formulation of amphotericin encapsulated

in liposomes. This renders the drug less toxic to the kidney than the parent compound. Each vial contains 50 mg amphotericin.

Uses

Severe systemic fungal infections, when conventional amphotericin is contraindicated because of toxicity, especially nephrotoxicity, or as a safer alternative to conventional amphotericin.

Administration

• IV: initially 1 mg/kg daily, if necessary to 3 mg/kg daily

Add 12 ml WFI to each 50-mg vial of liposomal amphotericin (4 mg/ml) Shake vigorously for at least 15 seconds

Calculate the amount of the 4 mg/ml solution required, i.e.:

100 mg 25 ml

150 mg 37.5 ml

200 mg 50 ml

300 mg 75 ml

Using the 5 micron filter provided add the required volume of the 4 mg/ml solution to at least equal volume of glucose 5% (final concen-tration 2 mg/ml) and given over 30–60 min

Although anaphylactic reactions rare, before starting treatment an ini-tial test dose of 1 mg should be given over 10 min, infusion stopped and patient observed for 30 min. Continue infusion if no signs of anaphyl-actic reaction

The diluted solution is stable for 24 hours Monitor: serum potassium and magnesium

In renal dialysis patients, give AmBisome at the end of each dialysis Although nephrotoxic, no dose adjustment is required in haemofiltration

How not to use liposomal amphotericin

Do not mix with other drugs

Adverse effects

Prevalence and severity lower than conventional amphotericin ↓

A

AMPHOTERICIN (LIPOSOMAL) – AmBisome

(44)

Cautions

Kidney disease

Concurrent use of nephrotoxic drugs

Diabetic patient: each vial contains 900 mg sucrose

A

(45)

AMPICILLIN

Ampicillin has a spectrum of activity, which includes staphylococci,

streptococci, most enterococci, Listeria monocytogenes and Gram ve

rods such as Salmonella spp., Shigella spp., E. coli, H. influenzae and

Proteus spp. It is not active against Pseudomnas aeruginosa and Klebsiella spp. However due to acquired resistance almost all staphylococci,

50% of E. coli and up to 15% of H. influenzae strains are now resistant. All penicillin-resistant pneumococci and enterococci have reduced susceptibility to ampicillin. Amoxicillin is similar but better absorbed orally.

Uses

Urinary tract infections Respiratory tract infections Invasive salmonellosis

Serious infections with Listeria monocytogenes, including meningitis

Penicillin hypersensitivity

Administration

• IV: 500 mg–1 g diluted in 10 ml WFI, 4–6 hourly over 3–5 min

• Meningitis caused by Listeria monocytogenes (with gentamicin)

IV: 2 g diluted in 10 ml WFI every 4 hours over 3–5 minutes.Treat for 10–14 days In renal impairment: 29 Dose (g) (range depending on severity of

CC (ml/min) infection) Interval (h)

10–20 500 mg–2 6

10 250 mg–1 6

How not to use ampicillin

Not for intrathecal use (encephalopathy)

Do not mix in the same syringe with an aminoglycoside (efficacy of aminoglycoside reduced)

Adverse effects

Hypersensitivity

Skin rash increases in patients with infectious mononucleosis (90%), chronic lymphocytic leukaemia and HIV infections (discontinue drug)

A

(46)

A

AMPICILLIN

Cautions

Severe renal impairment (reduce dose, rashes more common)

CVVH dose as for CC 10–20 ml/min, i.e. 500 mg–2 g every 6 hours. Not significantly cleared by PD or HD, dose as if CC 10 ml/min, i.e. 250 mg–1 g every 6 hours

(47)

ANIDULAFUNGIN (Ecalta)

Anidulafungin (Ecalta) is an echinocandin, similar to caspofungin and micafungin. It covers a wide range of Candida species causing invasive candidiasis (including C. krusei and C. glabrata) and is eliminated by nonenzymatic degradation to an inactive metabolite. The key distin-guishing features compared to caspofungin are simplicity of dosing reg-imen, storage at room temperature, narrower clinical indication and fewer drug interactions.

Uses

Invasive candidiasis in adult non-neutropenic patients

Hypersensitivity to echinocandin

Administration

• IV: Load with 200 mg on day 1, followed by 100 mg daily thereafter for a minimum of 14 days

Reconstitute each vial with 30 ml solvent provided, allowing up to 5 min for reconstitution. Add the reconstituted solution to a bag of sodium chloride 0.9% or glucose 5%, i.e. 100 mg in 250 ml and 200 mg in 500 ml. Administer at 3 ml/min

Available in vials containing 100 mg with solvent containing ethanol anhydrous in WFI

How not to use anidulafungin

Do not use in children under 18 years as insufficient data

Adverse effects Coagulopathy Convulsion Headache Increased creatinine Hypokalaemia Elevated LFT Flushing

Diarrhoea, nausea and vomiting Rash

Pruritus

Cautions

Hepatic failure worsening LFTs

The diluent contains the equivalent of 6 g of ethanol/100 mg of anidu-lafungin. Caution in breast feeding and pregnancy and high-risk groups, e.g. liver disease, epilepsy, alcoholism

Fructose intolerance

31

A

(48)

Organ failure

Renal: no dose adjustment necessary, as negligible renal clearance Hepatic: no dose adjustment, as not metabolised in liver

Unlikely to be removed by dialysis, therefore no dose adjustment required.

A

(49)

A

ATRACURIUM

33

ATRACURIUM

Atracurium is a non-depolarising neuromuscular blocker that is broken down by Hofmann degradation and ester hydrolysis.The ampoules have to be stored in the fridge to prevent spontaneous degradation.Atracurium has an elimination half-life of 20 min. The principal metabolite is lau-danosine, which can cause convulsions in dogs. Even with long-term infusions, the concentration of laudanosine is well below the seizure

threshold (17g/ml).It is the agent of choice in renal and hepatic failure.

Uses

Muscle paralysis

Airway obstruction

To facilitate tracheal intubation in patients at risk of regurgitation

Administration

• IV bolus: 0.5 mg/kg, repeat with 0.15 mg/kg at 20–45 min interval

• IV infusion: 0.2–0.4 mg/kg/h

Monitor with peripheral nerve stimulator

How not to use atracurium

As part of a rapid sequence induction In the conscious patient

By persons not trained to intubate trachea

Adverse effects

Bradycardia Hypotension

Cautions

Asthmatics (histamine release) Breathing circuit (disconnection) Prolonged use (disuse muscle atrophy)

Organ failure

Hepatic: increased concentration of laudanosine Renal: increased concentration of laudanosine

(50)

ATROPINE

The influence of atropine is most noticeable in healthy young adults in whom vagal tone is considerable. In infancy and old age, even large doses may fail to accelerate the heart.

Uses

Asystole (p. 241)

EMD or PEA with ventricular rate 60/min (p. 241) Sinus bradycardia – will increase BP as a result

Reversal of muscarinic effects of anticholinesterases (neostigmine) Organophosphate poisoning

Complete heart block Tachycardia

Administration

• Bradycardia: 0.3–1 mg IV bolus, up to 3 mg (total vagolytic dose),

may be diluted with WFI

• Asystole: 3 mg IV bolus, once only (p. 241)

• EMD or PEA with ventricular rate 60/min: 3 mg IV bolus, once

only (p. 241)

• Reversal of muscarinic effects of anticholinesterase: 1.2 mg for every 2.5 mg neostigmine

• Organophosphate poisoning: 1–2 mg initially, then further 1–2 mg every 30 min PRN

How not to use atropine

Slow IV injection of doses0.3 mg (bradycardia caused by medullary

vagal stimulation) Adverse effects Drowsiness, confusion Dry mouth Blurred vision Urinary retention Tachycardia

Pyrexia (suppression of sweating)

Atrial arrhythmias and atrioventricular dissociation (without significant cardiovascular symptoms)

Dose 5 mg results in restlessness and excitation, hallucinations,

delir-ium and coma

A

(51)

A

ATROPINE

35

Cautions

Elderly ( CNS side-effects)

Child with pyrexia (further temperature)

Acute myocardial ischaemia or MI (tachycardia may cause worsening) Prostatic hypertrophy–urinary retention (unless patient’s bladder catheterised)

Paradoxically, bradycardia may occur at low doses (0.3 mg)

Acute-angle glaucoma (further IOP) Pregnancy (foetal tachycardia)

↓ ↓ ↓

(52)

B

BENZYLPENICILLIN

Benzylpenicillin can only be given parenterally. It is active against most streptococci but the majority of strains of Staphylococcus aureus are resist-ant due to penicillinase production. Resistance rates are increasing in

Streptococcus pneumoniae, and benzylpenicillin should probably not be

used for empiric treatment of meningitis unless local levels of resistance are extremely low. All strains of Neisseria meningitidis remain sensitive.

Uses

• Infective endocarditis

• Streptococcal infections including severe necrotising soft tissue

infections and severe pharyngeal infections

• Pneumococcal infections – excluding empiric therapy of meningitis

• Gas gangrene and prophylaxis in limb amputation

• Meningococcal meningitis with sensitive organism

• Tetanus

• Post-splenectomy prophylaxis

Penicillin hypersensitivity

Administration

IV: 600–1200 mg diluted in 10 ml WFI, 6 hourly over 3–5 min, higher doses should be given for severe infections in 100 ml of glucose 5% or sodium chloride 0.9% and given over 30–60 min

Infective endocarditis: 7.2 g/24 h (with gentamicin) Adult meningitis: 14.4 g/24 h

Post-splenectomy prophylaxis: 600 mg 12 hourly Give at a rate not >300 mg/min

In renal impairment:

How not to use benzylpenicillin

Not for intrathecal use (encephalopathy)

Do not mix in the same syringe with an aminoglycoside (efficacy of aminoglycoside reduced)

CC (ml/min) Dose (range depending

on severity of infection)

10–20 600 mg–2.4 g every 6 hours 10 600 mg–1.2 g every 6 hours

(53)

Adverse effects

Hypersensitivity Haemolytic anaemia

Transient neutropenia and thrombocytopenia Convulsions (high-dose or renal failure)

Cautions

Anaphylactic reactions frequent (1:100 000)

Severe renal impairment (reduce dose, high doses may cause convulsions)

CVVH dose as for CC 10–20 ml/min (600 mg–2.4 g every 6 hours depending on severity of infection). Not significantly cleared by PD or HD, dose as if CC < 10 ml/min (600 mg–2.4 g every 6 hours depending on severity of infection).

B

BENZYLPENICILLIN

(54)

B

BUMET

ANIDE

BUMETANIDE

A loop diuretic similar to furosemide but 40 times more potent. Ototoxicity may be less with bumetanide than with furosemide, but nephrotoxicity may be worse.

Uses

Acute oliguric renal failure

May convert acute oliguric to non-oliguric renal failure. Other meas-ures must be taken to ensure adequate circulating blood volume and renal perfusion pressure

Pulmonary oedema secondary to acute left ventricular failure Oedema associated with congestive cardiac failure, hepatic failure and renal disease

Oliguria secondary to hypovolaemia

Administration

• IV bolus: 1–2 mg 1–2 min, repeat in 2–3 h if needed

• IV infusion: 2–5 mg in 100 ml glucose 5% or sodium chloride 0.9%

saline, given over 30–60 min

Adverse effects

Hyponatraemia, hypokalaemia, hypomagnesaemia Hyperuricaemia, hyperglycaemia Hypovolaemia Ototoxicity Nephrotoxicity Pancreatitis Cautions

Amphotericin (increased risk of hypokalaemia)

Aminoglycosides (increased nephrotoxicity and ototoxicity) Digoxin toxicity (due to hypokalaemia)

Organ failure

Renal: may need to increase dose for effect

(55)

C

CASPOFUNGIN (Cancidas)

39

CASPOFUNGIN (Cancidas)

Caspofungin covers a wider range of Candida species causing invasive candidiasis than fluconazole and is active against Aspergillus species. It has a better side-effect profile than amphotericin. Side-effects are typically mild and rarely lead to discontinuation.

Uses Invasive candidiasis Invasive aspergillosis Contraindications Breastfeeding Administration

• IV: Load with 70 mg on day 1, followed by 50 mg daily thereafter

typically for a minimum of 14 days

If 80 kg, continue with maintenance dose of 70 mg daily Reconstitute with 10 ml WFI. Add the reconstituted solution to a 100 ml or 250 ml bag of sodium chloride 0.9% or Hartmann’s solution, given over 1 hour.

Available in vials containing 50 mg and 70 mg powder. Store vials in fridge at 2–8°C.

How not to use caspofungin

Do not use diluents containing glucose

Adverse effects Thrombophlebitis Fever Headache Tachycardia Anaemia

Decreased platelet count Elevated LFT

Hypokalaemia Hypomagnesaemia

Cautions

Co-administration with the inducers efavirenz, nevirapine, rifampicin, dexamethasone, phenytoin or carbamazepine may result in a decrease in caspofungin AUC, so increase in the daily dose of caspofungin to 70 mg. Ciclosporin increases the AUC of caspofungin by approximately 35%. Caspofungin lowers trough concentrations of tacrolimus by 26%

(56)

Initially, rifampicin causes a 170% increase in trough concentration of caspofungin on the first day of co-administration; after 2 weeks trough levels of caspofungin are reduced by 30%

Organ failure

Renal: No dose adjustment necessary

Hepatic: Mild (Child–Pugh score 5–6): no dose adjustment

Moderate (Child-Pugh score 7–9): 70 mg loading followed by 35 mg daily

Severe (Child-Pugh score 9): no data

Organ replacement therapy

Not removed by dialysis

C

(57)

C

CEFOT

AXIME

41

Infection Dose (g) Interval (h)

Mild–moderate 1 12

Moderate–serious 2 8

Life-threatening 3 6

CEFOTAXIME

A third-generation cephalosporin with enhanced activity against Gram ve species in comparison with second-generation cephalosporins. It is not active against Pseudomonas aeruginosa, enterococci or Bacteroides spp. Use is increasingly being compromised by the emergence of Gram ve strains expressing extended spectrum beta-lactamases (ESBLs) and chromosomal beta-lactamase producers.

Uses

Surgical prophylaxis, although first- and second-generation cephalosporins are usually preferred

Acute epiglottitis due to Haemophilus influenzae Empiric therapy of meningitis

Intra-abdominal infections including peritonitis Community-acquired and nosocomial pneumonia Urinary tract infections

Sepsis of unknown origin

Hypersensitivity to cephalosporins

Serious penicillin hypersensitivity (10% cross-sensitivity) Porphyria

Administration

• IV: 1 g 12 hourly, increased in life-threatening infections (e.g.

menin-gitis) to 3 g 6 hourly

Reconstitute with 10 ml WFI, given over 3–5 min

Adverse effects

Hypersensitivity Transient LFTs

Clostridium difficile-associated diarrhoea

(58)

C

CEFOT

AXIME

Cautions

Concurrent use of nephrotoxic drugs (aminoglycosides, loop diuretics) Severe renal impairment (halve dose)

False ve urinary glucose (if tested for reducing substances)

False ve Coombs’ test

Organ failure

Renal: In severe renal impairment (10 ml/min): 1 g every 8-12 hours

(59)

C

CEFT

AZIDIME

43

CEFTAZIDIME

A third-generation cephalosporin whose activity against Gramve

organisms,most notably S.aureus,is diminished in comparison with

second-generation cephalosporins, while action against Gramve organisms,

including Pseudomonas aeruginosa, is enhanced. Ceftazidime is not active against enterococci, MRSA or Bacteroides spp.

Uses

Acute epiglottitis due to Haemophilus influenzae Meningitis due to Pseudomonas aeruginosa Intra-abdominal infections including peritonitis Nosocomial pneumonia

Urinary tract infections Severe sepsis of unknown origin Febrile neutropenia

Administration

• IV: 2 g 8 hourly

Reconstitute with 10 ml WFI, given over 3–5 min

CC (ml/min) Dose (g) Interval (h)

31–50 1–2 12

16–30 1–2 24

6–15 0.5–1 24

5 0.5–1 48

Infection Dose (g) Interval (h)

Mild–moderate 0.5–1 12 Moderate–serious 1 8 Life-threatening 2 8 In renal impairment: Adverse effects Hypersensitivity Transient LFTs

(60)

C

CEFT

AZIDIME

Cautions

Renal impairment (reduce dose)

Concurrent use of nephrotoxic drugs (aminoglycosides, loop diuretics) False ve urinary glucose (if tested for reducing substances)

False ve Coombs’ test

CVVH dialysed, 2 g every 8 hours or 1–2 g every 12 hours. PD dialysed 500 mg–1 g every 24 hours. HD dialysed 500 mg–1 g every 24–48 hours.

(61)

C

CEFTRIAXONE

45

CEFTRIAXONE

A third-generation cephalosporin which is similar in many respects to

cefotaxime, with enhanced activity against Gram ve species in

com-parison to second generation cephalosporins. Ceftriaxone is not active against enterococci, MRSA, Pseudomonas aeruginosa or Bacteroides spp. Ceftriaxone has a prolonged serum half-life allowing for once-daily dosing. However, twice daily dosing is normally recommended for severe infections including meningitis.

Uses

Empiric therapy for meningitis

Intra-abdominal infections including peritonitis Community-acquired or nosocomial pneumonia

Surgical prophylaxis, although first- and second-generation

cephalosporins are usually preferred

Clearance of throat carriage in meningococcal disease

Administration

• IV: 2 g once daily, increased to 2 g 12 hourly in severe infections

Reconstitute 2-g vial with 40 ml of glucose 5% or sodium chloride 0.9% given over at least 30 min

In renal impairment:

How not to use ceftriaxone

Not to be dissolved in infusion fluids containing calcium (Hartmann’s)

Adverse effects

Hypersensitivity

Transient liver enzymes

↓

(62)

C

CEFUROXIME

A second-generation cephalosporin widely used in combination with metronidazole in the postoperative period following most abdominal procedures. Has greater activity against Staphylococcus aureus (including penicillinase-producing strains) compared with the third-generation cephalosporins, but not active against MRSA, enterococcus, Pseudomonas

aeruginosa or Bacteroides spp. It also has poor activity against

penicillin-resistant strains of Streptococcus pneumoniae.

Uses

Surgical prophylaxis

Acute epiglottitis due to Haemophilus influenzae Intra-abdominal infections including peritonitis Community-acquired and nosocomial pneumonia Urinary tract infections

Patients admitted from the community with sepsis of unknown origin Soft tissue infections

Serious penicillin hypersensitivity (10% cross-sensitivity) Meningitis (high relapse rate)

Porphyria

Administration

• IV: 0.75–1.5 g 6–8 hourly

Reconstitute with 20 ml WFI, given over 3–5 min In renal impairment:

20–50 0.75–1.5 8 10–20 0.75–1.5 8–12 10 0.75–1.5 12–24 Adverse effects Hypersensitivity Transient LFTs

Cautions

Hypersensitivity to penicillins Renal impairment

CVVH dialysed, dose as for GFR 10–20 ml/min, i.e. 750 mg–1.5 g IV

8–12 hourly. For PD and HD dose as in CC 10 ml/min, i.e. 750 mg to

(63)

C

CHLORDIAZEPOXIDE

47

CHLORDIAZEPOXIDE

Chlordiazepoxide is a benzodiazepine used to attenuate alcohol with-drawal symptoms, but also has a dependence potential. The risk of dependence is minimised by limiting the duration of treatment and reducing the dose gradually over 7–14 days. It is available as 5-mg and 10-mg capsules or tablets.

Uses

Alcohol withdrawal Restlessness and agitation

Alcohol-dependent patients who continue to drink Obstructive sleep apnoea

Severe hepatic impairment

Administration

• Alcohol withdrawal Orally:

• Restlessness and agitation

Orally: 10–30 mg 3 times daily

How not to use chlordiazepoxide

Prolonged use (risk of dependence) Abrupt withdrawal Dose (mg) at: Day 08:00 h 12:00 h 18:00 h 22:00 h 1 30 30 30 30 2 25 25 25 25 3 20 20 20 20 4 10 10 10 10 5 5 5 5 5 6 – 5 5 5 7 – – 5 5 8 – – – 5

(64)

Adverse effects Muscle weakness Confusion Ataxia Hypotension Cautions

Concurrent use of other CNS depressants will produce excessive sedation

Cardiac and respiratory disease – confusion may indicate hypoxia Hepatic impairment – sedation can mask hepatic coma (avoid if severe) Renal impairment – increased cerebral sensitivity

Organ failure

Hepatic: reduced clearance with accumulation. Can precipitate coma Renal: increased cerebral sensitivity

C

(65)

C

CICLOSPORIN

49

CICLOSPORIN

Ciclosporin is a cyclic peptide molecule derived from a soil fungus. It is a potent nephrotoxin, producing interstitial renal fibrosis with tubu-lar atrophy. Monitoring of ciclosporin blood level is essential.

Normal range: 100–300µg/l

For renal transplants: lower end of range For heart/lung/liver: upper end of range

For stem cell transplant: 200–600µg/l – dependent upon donor,

con-ditioning regimen and T-depletion of graft

Uses

Prevention of organ rejection after transplantation

Administration

• IV dose: 1–5 mg/kg/day

To be diluted 1 in 20 to 1 in 100 with 0.9% sodium chloride or 5% glucose

To be given over 2–6 h

Infusion should be completed within 12 h if using PVC lines Switch to oral for long-term therapy

• Oral: 1.5 times IV dose given 12 hourly Monitor: Hepatic function

Renal function

Ciclosporin blood level (pre-dose sample)

How not to use ciclosporin

Must not be given as IV bolus

Do not infuse at 12 h if using PVC lines – leaching of phthalates from the PVC

Adverse effects

Enhanced renal sensitivity to insults

Plasma urea and serum creatinine secondary to glomerulosclerosis Hypertension – responds to conventional antihypertensives Hepatocellular damage ( transaminases)

Hyperuricaemia Gingival hypertrophy Hirsutism

Tremors or seizures at high serum levels

Cautions

Susceptibility to infections and lymphoma

Nephrotoxic effects with concurrent use of other nephrotoxic drugs ↓

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